Building on dendritic cell subsets to improve cancer vaccines

Abstract

T cells can reject established tumors when adoptively transferred into patients, thereby demonstrating that the immune system can be harnessed for cancer therapy. However, such passive immunotherapy is unlikely to maintain memory T cells that might control tumor outgrowth on the long term. Active immunotherapy with vaccines has the potential to induce tumor-specific effector and memory T cells. Vaccines act through dendritic cells (DCs) which induce, regulate, and maintain T cell immunity. Clinical trials testing first generation DC vaccines pulsed with tumor antigens provided a proof-of-principle that therapeutic immunity can be elicited. The increased knowledge of the DC system, including the existence of distinct DC subsets is leading to new trials which aim at improved immune and clinical outcomes.

Figure 1. Distinct subsets of myeloid dendritic cells induce distinct types of immune responses

Human LCs induce potent CTL responses, possibly via IL-15: At least four lines of evidence indicate that LCs are remarkable at inducing CTL responses: 1) LCs loaded with an HLA class I peptide potently induce the proliferation of peptide-specific naïve CD8+ T cells; 2) LCs expand naïve CD8⁺ T cells with high avidity against peptide/HLA-I complex; 3) Naive CD8⁺ T cells primed by LCs express high levels of cytotoxic molecules, such as granzymes A, B, and perforin, and display a high cytotoxicity; and 4) LCs are efficient at cross-presentation of antigens. Human CD14+ dermal DCs induce potent humoral responses via IL-12: When DCs form the complex with T cells and B cells at extrafollicular sites, IL-12 derived from activated DCs promotes B cells to differentiate into ASCs by two different paths: a direct path via DC-B interaction, and an indirect path through induction of IL-21-producing Tfh-like cells. We envision that targeting antigens and activation of distinct mDC subsets, with different specializations, will result in the generation of a broad and long lived immune protection. Thus, the most efficient vaccines might be those that will target both LCs and dermal CD14⁺ DCs thereby allowing the maximal stimulation of cellular and humoral immune responses and the generation of long-term memory protection.

Figure 2. Building on dendritic Cell Subsets to Improve Cancer Vaccines

First generation vaccines: Early clinical trials with first generation DC vaccines (left panel) showed the induction of immune responses to vaccine antigens. However, the clinical responses are still infrequent. Possible contributing factors can be grouped into: i) vaccine features, and ii) suppressive pathways established by tumors. Vaccine features include: i) insufficient CD4⁺ T cell help; ii) generation of low affinity CTLs; and iii) generation of T regs. Suppressive pathways involve: i) suppressor cells, both T regs as well as myeloid suppressor cells; ii) suppressor molecules expressed by tumors such as PD-L1; and iii) suppressive factors secreted by tumors, for example TGF-β or VEGF. All these act in concert to inhibit the CTL function including inhibiting the release of cytotoxic effector molecules Granzyme B and perforin. New generation DC vaccines: Improved next generation DC vaccines will harness Langerhans cells and microbial activation signals leading to: i) secretion of high amounts of cytokines such as IL-12, which will generate strong Th1 response and helper function for generation of memory T cells; and IL-15 which will help generation of high avidity CTLs that might be resistant to tumor microenvironment; and ii) strong costimulation mediated via at least three molecular pathways such as CD80, CD70 and 4-1BB. This in combination with therapies that will permit to eliminate T regs and block tumor microenvironment will results in the full activity of elicited CTLs and tumor rejection.

Figure 3. Approaches to DC-based immune intervention in cancer

1) Vaccines based on antigen with or without adjuvant that target DCs randomly. That might result in vaccine antigens being taken up by a “wrong” type of DCs in the periphery which might lead to “unwanted” type of immune response. Vaccine antigens could also flow to draining lymph nodes where they can be captured by resident DCs; 2) Vaccines based on ex-vivo generated tumor antigen-loaded DCs that are injected back into patients; and 3) specific in vivo DC targeting with anti-DC antibodies fused with antigens and with DC activators. 4) Next generation clinical trials will test combination therapies to offset tumor-induced suppression.